The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease

Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18528-18536. doi: 10.1073/pnas.1907563116. Epub 2019 Aug 27.

Abstract

T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

Keywords: autoimmunity; nuclear receptors; transcriptional repressor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / immunology
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Genetic Loci
  • HEK293 Cells
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Transgenic
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / immunology
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use
  • RNA-Seq
  • Response Elements / genetics
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use

Substances

  • Il17a protein, mouse
  • Il17f protein, mouse
  • Interleukin-17
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Pyrrolidines
  • Rorc protein, mouse
  • SR9009
  • Thiophenes